Method of intradermally injecting substances

ABSTRACT

A method of making an intradermal injection using a drug delivery device containing the substance to be injected. A device for practicing the method includes a needle cannula having a forward tip and a limiter portion having a skin engaging surface surrounding the needle cannula. The needle cannula is in fluid communication with the substance and the tip of the needle cannula extends beyond the skin engaging surface a distance equal to approximately 0.5 mm to 3.0 mm. The needle cannula includes a fixed angle of orientation relative to the plane of the skin engaging surface. The skin engaging surface limits penetration of the needle tip into the skin so that the substance can be expelled through the needle tip into the dermis layer. Preferably, the fixed angle of orientation of the needle cannula is generally perpendicular relative to the skin surface, and the skin engaging surface is generally flat.

REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation U.S. patent applicationSer. No. 10/044,504 filed on Jan. 10, 2002, which is acontinuation-in-part of U.S. patent application Ser. No. 09/835,243,filed on Apr. 13, 2001, which is a continuation-in-part of U.S. patentapplication Ser. No. 09/417,671, filed on Oct. 14, 1999.

FIELD OF THE INVENTION

[0002] The present invention generally relates to a method fordelivering substances such as drugs, vaccines and the like used in theprevention, diagnosis, alleviation, treatment, or cure of diseases intothe skin of an animal using an injection device having a needle cannulaand a limiter for engaging the surface of the skin and limitingpenetration of the tip of the needle cannula into the skin, and morespecifically to a method for injecting such substances intradermally,i.e., preferably from approximately 1.0 mm to approximately 2.0 mm, andmost preferably around 1.5 mm±0.2 mm to 0.3 mm, such that the substanceis injected into the dermis layer of the animal. In addition, the methodof the present invention includes fixing the orientation of the needlecannula, i.e., so that the needle cannula is preferably generallyperpendicular to the plane of the skin engaging surface of the limiterwithin about fifteen degrees, and the skin engaging surface is generallyflat.

BACKGROUND OF THE INVENTION

[0003] Intradermal injections are used for delivering a variety ofsubstances. Many of these substances have proven to be more effectivelyabsorbed into or react with the immune response system of the body wheninjected intradermally. Recently, clinical trials have shown thathepatitis B vaccines administered intradermally are more imunogenic thanif administered intramuscularly. In addition, substances have beeninjected intradermally for diagnostic testing, such as, for exampleusing what is known in the art as the “Mantoux test” to determine theimmunity status of the animal against tuberculosis and the immediatehypersensitivity status of Type I allergic diseases.

[0004] An intradermal injection is made by delivering the substance intothe epidermis and upper layers of the dermis. Below the dermis layer issubcutaneous tissue (also sometimes referred to as the hypodermis layer)and muscle tissue, in that order. There is considerable variation in theskin thickness both between individuals and within the same individualat different sites of the body. Generally, the outer skin layer,epidermis, has a thickness between 50-200 microns, and the dermis, theinner and thicker layer of the skin, has a thickness between 1.5-3.5 mm.Therefore, a needle cannula that penetrates the skin deeper than about3.0 mm has a potential of passing through the dermis layer of the skinand making the injection into the subcutaneous region, which may resultin an insufficient immune response, especially where the substance to bedelivered intradermally has not been indicated for subcutaneousinjection. Also, the needle cannula may penetrate the skin at tooshallow a depth to deliver the substance and result in what is commonlyknown in the art as a “wet injection” because of reflux of the substancefrom the injection site.

[0005] The standard procedure for making an intradermal injection isknown to be difficult to perform, and therefore dependent uponexperience and technique of the healthcare worker. This procedure isrecommended to be performed by stretching the skin, orienting the bevelof a 26 Gauge short bevel needle cannula upwardly and inserting theneedle cannula to deliver a volume of 0.5 ml or less of the substanceinto the skin of an animal with the needle cannula being inserted intothe skin at an angle varying from around 10-15 degrees relative to theplane of the skin to form a blister or wheal in which the substance isdeposited or otherwise contained. Accordingly, the technique utilized toperform the standard intradermal injection is difficult and requires theattention of a trained nurse or medical doctor. This procedure alsomakes it essentially impossible to self-administer an intradermalinjection. Inserting the needle to a depth greater than about 3.0 mmtypically results in a failed intradermal injection because thesubstance being expelled through the cannula will be injected into thesubcutaneous tissue of the animal. Further, the present method is notsuitable for self-administration of intradermal injections.

[0006] The most frequent cause of a failed intradermal injection isderived from inserting the needle into the skin at an angle greater than15 degrees. A further cause of error is derived from pinching ratherthan stretching the skin in the area of the injection, which is normallydone when giving a subcutaneous rather than an intradermal injection.Pinching increases the likelihood of giving a subcutaneous injection.Procedural errors as described above result in delivering the contentsof the injection into the subcutaneous layer, which can reduce theeffectiveness of the injection, as well as possibly deliver thesubstance in a way not approved for delivery. Intradermal injectionsperformed by using the standard procedure also are known to cause asignificant amount of pain to the recipient of the injection because theneedle cannula is inserted into the skin at an angle of about 10-15degrees. By inserting the needle cannula at this angle, about 5 mm toabout 6 mm of the needle is actually inserted into the skin. Thisresults in a significant disruption of the pain receptors dispersedthroughout the upper layers of the skin.

[0007] Accordingly, there has been a long felt need for a simplifiedmethod of performing an intradermal injection of substances whichovercomes the problems and limitations associated with conventionalmethods, especially including reducing the probability of error and paincaused from the injection by making such injections less dependent uponexperience and technique. In addition, there has been a need to limitthe depth of penetration of the needle cannula into the skin of theanimal to avoid entry into the subcutaneous layer of the skin as well asreliably fixing the orientation of the needle cannula relative to theskin. Also, there has been a need to apply pressure to the skin of theanimal to facilitate formation of the blister or wheal in the skin inwhich the substance is deposited or otherwise contained and avoid wetinjections.

SUMMARY OF THE INVENTION AND ADVANTAGES

[0008] In contrast to the conventional methods discussed above, it hasbeen found by the applicant that a method of intradermally injectingsubstances into the skin to obtain systemic delivery or an immuneresponse can be used in accordance with the present invention toeffectively and reliably deliver such substances intradermally.Specifically, the method includes fixing the orientation of the needlecannula relative to the skin and engaging the surface of the skin tolimit the depth of penetration of the needle cannula into the skin,i.e., preferably from approximately 1.0 mm to approximately 2.0 mm, andmost preferably around 1.5 mm±0.2 mm to 0.3 mm, to avoid entry into thesubcutaneous layer. In addition, the method includes applying pressureto the surface of the skin to facilitate delivery of the substance,particularly formation of a blister or wheal in the skin in which thesubstance is deposited or otherwise contained. Further, the pressureapplied masks the pain derived from the intradermal injection bystimulating the muscle fibers to block the pain receptors. Manysubstances have proven to be more effective when injected intradermallyin the prevention, diagnosis, alleviation, treatment, or cure ofdiseases. These include several drugs and vaccines such as, for example,influenza vaccines, hepatitis B vaccine, rabies vaccines tuberculin testsubstance and many others. These vaccines, drugs and the like willhereinafter be referred to as substances. It is also possible toself-administer intradermal injections by the method of this invention.

[0009] The hypodermic needle assembly set forth above includes theelements necessary to perform the present invention directed to animproved method of making an intradermal injection into the skin of ananimal including the steps of providing a drug delivery device includinga needle cannula having a forward needle tip and the needle cannulabeing in fluid communication with a substance contained in the drugdelivery device and including a limiter portion surrounding the needlecannula and the limiter portion including a skin engaging surface, withthe needle tip of the needle cannula extending from the limiter portionbeyond the skin engaging surface a distance equal to approximately 0.5mm to approximately 3.0 mm and the needle cannula having a fixed angleof orientation relative to a plane of the skin engaging surface of thelimiter portion, inserting the needle tip into the skin of an animal andengaging the surface of the skin with the skin engaging surface of thelimiter portion, such that the skin engaging surface of the limiterportion limits penetration of the needle cannula tip into the dermislayer of the skin of the animal, and expelling the substance from thedrug delivery device through the needle cannula tip into the skin of theanimal to expose the injected substance to the microcirculatory bloodvasculature and the lymphatic plexuses.

[0010] In the preferred method, the substance is selected from the groupconsisting of drugs, vaccines and the like used in the prevention,diagnosis, alleviation, treatment, or cure of diseases. In addition, thefixed angle of orientation of the needle cannula is further defined asbeing generally perpendicular to the plane of the skin engaging surfaceof the limiter portion within about fifteen degrees, and most preferablywithin about five degrees, substantially ninety degrees relative to theplane of the skin engaging surface of the limiter portion. In addition,the drug delivery device includes a syringe having a barrel and aplunger rod preferably including a stopper received within the barreltherein and the plunger rod being depressable to expel the substancefrom the delivery device through the tip of the needle cannula, with thebarrel including a barrel tip and the needle cannula forms part of aneedle assembly attachable to and in fluid communication with the barreltip.

[0011] Also, the preferred embodiment of the method includes the step ofselecting an injection sight on the skin of the animal and includes thestep of cleaning the injection sight on the skin of the animal prior toexpelling the substance from the drug delivery device into the skin ofthe animal. In addition, the method includes the step of filling thedrug delivery device with the substance. Further, the method includesthe steps of pressing the skin engaging surface of the limiter portionagainst the skin of the animal and applying pressure, thereby stretchingthe skin of the animal, and withdrawing the needle cannula from the skinafter injecting the substance. Still further, the step of inserting theforward tip into the skin is further defined by inserting the forwardtip into the skin to a depth of from approximately 1.0 mm toapproximately 2.0 mm, and most preferably into the skin to a depth of1.5 mm±0.2 to 0.3 mm. The preferred substance comprises an influenzavaccine, a hepatitis B vaccine, a rabies vaccine, a cancer vaccine, agenetic based vaccine or a tuberculin test substance.

[0012] The preferred substance includes a combination of the drugs orvaccines. In addition, the preferred method includes the addition of asubstance selected from a combination of vaccines against: (i) measles,mumps and rubella, (ii) diphtheria, tetanus and acellular pertussis,(iii) hepatitis A and hepatitis B, (iv) haemophilus influenza B,diphtheria, tetanus and acellular pertussis, (v) haemophilus influenzaB, hepatitis B, diphtheria, tetanus and a cellular pertussis, and (vi)haemophilus influenza B, inactivated polio, diphtheria, tetanus andacellular pertussis, which are commonly delivered in combination to thesubcutaneous and/or intramuscular space.

[0013] In addition, the present invention is directed to a method ofmaking an intradermal injection with a drug delivery device having alimiter with a skin engaging surface limiting the depth a needle cannulacan be inserted into the skin of an animal to obtain systemic deliveryor an immune response or including the steps of exposing a forward tipof the needle cannula extending from a limiter beyond a skin engagingsurface a distance equal to approximately 0.5 mm to approximately 3.0 mmand the needle cannula having a fixed angle of orientation relative tothe skin engaging surface of the limiter, inserting the forward tip ofthe needle cannula into the skin of the animal at until the skinengaging surface contacts the skin of the animal, and expelling asubstance from the device into the dermis layer of the skin of theanimal to expose the injected substance to the microcirculatory bloodvasculature and the lymphatic plexuses.

[0014] In the preferred embodiment of the method, the step of insertingthe forward tip into the skin of the animal is further defined byinserting the forward tip into the skin at an angle being generallyperpendicular to the skin within about fifteen degrees, with the anglemost preferably being generally ninety degrees to the skin, within aboutfive degrees, and the fixed angle of orientation relative to the skinengaging surface is further defined as being generally perpendicular. Inthe preferred embodiment, the limiter surrounds the needle cannula,having a generally planar flat skin engaging surface. Also, the drugdelivery device comprises a syringe having a barrel and a plungerreceived within the barrel and the plunger being depressable to expelthe substance from the delivery device through the forward tip of theneedle cannula.

[0015] In the preferred embodiment of the method of the presentinvention, expelling the substance from the delivery device is furtherdefined by grasping the hypodermic needle with a first hand anddepressing the plunger with an index finger of a second hand andexpelling the substance from the delivery device by grasping thehypodermic needle with a first hand and depressing the plunger on thehypodermic needle with a thumb of a second hand, with the step ofinserting the forward tip into the skin of the animal further defined bypressing the skin of the animal with the limiter. In addition, themethod may includes the step of attaching a needle assembly to a tip ofthe barrel of the syringe with the needle assembly including the needlecannula and the limiter, and includes the step of exposing the tip ofthe barrel before attaching the needle assembly thereto by removing acap from the tip of the barrel. Alternatively, the step of inserting theforward tip of the needle into the skin of the animal may be furtherdefined by simultaneously grasping the hypodermic needle with a firsthand and pressing the limiter against the skin of the animal therebystretching the skin of the animal, and expelling the substance bydepressing the plunger with an index finger of the first hand orexpelling the substance by depressing the plunger with a thumb of thefirst hand. The method further includes withdrawing the forward tip ofthe needle cannula from the skin of the animal after the substance hasbeen injected into the skin of the animal. Still further, the methodincludes inserting the forward tip into the skin preferably to a depthof from approximately 1.0 mm to approximately 2.0 mm, and mostpreferably to a depth of 1.5 mm±0.2 to 0.3 mm. Also, the step ofexpelling the substance from the device into the dermis layer of theskin includes expelling a small volume of air from the device into thedermis layer before expelling the substance.

[0016] Also, the substance intradermally delivered in accordance withthe method of the present invention is selected from the groupconsisting of drugs, vaccines and the like used in the prevention,diagnosis, alleviation, treatment, or cure of disease, with the drugsincluding Alpha-1 anti-trypsin, Anti-Angiogenesis agents, Antisense,butorphanol, Calcitonin and analogs, Ceredase, COX-II inhibitors,dermatological agents, dihydroergotamine, Dopamine agonists andantagonists, Enkephalins and other opioid peptides, Epidermal growthfactors, Erythropoietin and analogs, Follicle stimulating hormone,G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs(including growth hormone releasing hormone), Growth hormoneantagonists, Hirudin and Hirudin analogs such as hirulog, IgEsuppressors, Insulin, insulinotropin and analogs, Insulin-like growthfactors, Interferons, Interleukins, Leutenizing hormone, Leutenizinghormone releasing hormone and analogs, Low molecular weight heparin,M-CSF, metoclopramide, Midazolam, Monoclonal antibodies, Narcoticanalgesics, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissueplasminogen activators, TNF-, and TNF- antagonist, the vaccines, with orwithout carriers/adjuvants, including prophylactics and therapeuticantigens (including but not limited to subunit protein, peptide andpolysaccharide, polysaccharide conjugates, toxoids, genetic basedvaccines, live attenuated, reassortant, inactivated, whole cells, viraland bacterial vectors) in connection with, addiction, arthritis,cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease,meningococcus, measles, mumps, rubella, varicella, yellow fever,Respiratory syncytial virus, tick borne japanese encephalitis,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and E, otitis media, rabies, polio, HIV,parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia,non-typeable haemophilus, moraxella catarrhalis, human papilloma virus,tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosismalaria, E-coli, Alzheimers, H. Pylori, salmonella, diabetes, cancer,herpes simplex, human papilloma and the like other substances includingall of the major therapeutics such as agents for the common cold,Anti-addiction, anti-allergy, anti-emetics, anti-obesity,antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antihistamines, anti-inflammatory agents,antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, vasodilators, including general, coronary, peripheral andcerebral, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents.

[0017] Another embodiment of the method of the present invention ofmaking an intradermal injection into the skin of an animal includes thesteps of providing a drug delivery device with a prefillable containerincluding a needle cannula having a forward needle tip and the needlecannula being in fluid communication with a substance contained in theprefillable container and including a limiter portion surrounding theneedle cannula and the limiter portion including a skin engagingsurface, with the needle tip of the needle cannula extending from thelimiter portion beyond the skin engaging surface and the needle cannulahaving a fixed angle of orientation relative to a plane of the skinengaging surface of the limiter portion, inserting the needle tip intothe skin of an animal and engaging the surface of the skin with the skinengaging surface of the limiter portion such that the skin engagingsurface of the limiter portion limits penetration of the needle tip intothe dermis layer of the skin of the animal, and expelling a small volumeof air and the substance from the drug delivery device through theneedle tip into the skin of the animal to expose the injected substanceto the microcirculatory blood vascularity and the lymphatic plexuseswhere the substance can be taken up, absorbed or can interact with thecells to obtain systemic delivery or an immune response in cases wherethe substance is either a drug or one or more vaccines.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Other advantages of the present invention will be readilyappreciated and apparent to those skilled in the art as the same becomesbetter understood by reference to the following detailed descriptionwhen considered in connection with the accompanying drawings wherein:

[0019]FIG. 1 is an exploded, perspective illustration of a needleassembly designed according to this invention.

[0020]FIG. 2 is a partial cross-sectional illustration of the embodimentof FIG. 1.

[0021]FIG. 3 shows the embodiment of FIG. 2 attached to a syringe bodyto form an injection device.

[0022]FIG. 4 is a perspective view of one technique for making theintradermal injection of the present invention.

[0023]FIG. 5 is a perspective view of a second technique for making theintradermal injection of the present invention.

[0024]FIG. 6 is a perspective view of a third technique for making theintradermal injection of the present invention.

[0025]FIG. 7 is a perspective view of a fourth technique for making theintradermal injection of the present invention.

[0026]FIG. 8 is a bar chart showing the B-gal expression levels of theclinical trials on swine skin.

[0027]FIG. 9 is a histogram showing the results of a survey of thesubjects pain perception relevant from the human clinical trial.

[0028]FIG. 10 is a flow chart diagram that schematically illustratespreparation of the device for use in intradennally injecting substances,including filling the device with the substance.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] FIGS. 1-3 of the drawings illustrate an example of a drugdelivery device which can be used to practice the methods of the presentinvention for making intradermal injections illustrated in FIGS. 4-7.The device 10 illustrated in FIGS. 1-3 includes a needle assembly 20which can be attached to a syringe barrel 60. Other forms of deliverydevices may be used including pens of the types disclosed in U.S. Pat.No. 5,279,586, U.S. patent application Ser. No. 09/027,607 and PCTApplication No. WO 00/09135, the disclosure of which are herebyincorporated by reference in their entirety. The method of the presentinvention can be used to intradermally inject substances, other thanfood, such as drugs, vaccines and the like used in the prevention,diagnosis, alleviation, treatment, or cure of disease into the skin ofan animal such as a human, referred to collectively herein as“substances”.

[0030] The needle assembly 20 includes a hub 22 that supports a needlecannula 24. The limiter 26 receives at least a portion of the hub 22 sothat the limiter 26 generally surrounds the needle cannula 24 as bestseen in FIG. 2.

[0031] One end 30 of the hub 22 is able to be secured to a receiver 32of a syringe. A variety of syringe types for containing the substance tobe intradermally delivered according to the present invention can beused with a needle assembly designed, with several examples being givenbelow. The opposite end of the hub 22 preferably includes extensions 34that are nestingly received against abutment surfaces 36 within thelimiter 26. A plurality of ribs 38 preferably are provided on thelimiter 26 to provide structural integrity and to facilitate handlingthe needle assembly 20.

[0032] By appropriately designing the size of the components, a distance“d” between a forward end or tip 40 of the needle 24 and a skin engagingsurface 42 on the limiter 26 can be tightly controlled. The distance “d”preferably is in a range from approximately 0.5 mm to approximately 3.0mm, and most preferably around 1.5 mm±0.2 mm to 0.3 mm. When the forwardend 40 of the needle cannula 24 extends beyond the skin engaging surface42 a distance within that range, an intradermal injection is ensuredbecause the needle is unable to penetrate any further than the typicaldermis layer of an animal. Typically, the outer skin layer, epidermis,has a thickness between 50-200 microns, and the dermis, the inner andthicker layer of the skin, has a thickness between 1.5-3.5 mm. Below thedermis layer is subcutaneous tissue (also sometimes referred to as thehypodermis layer) and muscle tissue, in that order.

[0033] As can be best seen in FIG. 2, the limiter 26 includes an opening44 through which the forward end 40 of the needle cannula 24 protrudes.The dimensional relationship between the opening 44 and the forward end40 can be controlled depending on the requirements of a particularsituation. In the illustrated embodiment, the skin engaging surface 42is generally planar or flat and continuous to provide a stable placementof the needle assembly 20 against an animal's skin. Although notspecifically illustrated, it may be advantageous to have the generallyplanar skin engaging surface 42 include either raised portions in theform of ribs or recessed portions in the form of grooves in order toenhance stability or facilitate attachment of a needle shield to theneedle tip 40. Additionally, the ribs 38 along the sides of the limiter26 may be extended beyond the plane of the skin engaging surface 42.

[0034] Regardless of the shape or contour of the skin engaging surface42, the preferred embodiment includes enough generally planar or flatsurface area that contacts the skin to facilitate stabilizing theinjector relative to the animal's skin. In the most preferredarrangement, the skin engaging surface 42 facilitates maintaining theinjector in a generally perpendicular orientation relative to the skinsurface and facilitates the application of pressure against the skinduring injection. Thus, in the preferred embodiment, the limiter hasdimension or outside diameter of at least 5 mm. The major dimension willdepend upon the application and packaging limitations, but a convenientdiameter is less than 15 mm or more preferably 11-12 mm.

[0035] It is important to note that although FIGS. 1 and 2 illustrate atwo-piece assembly where the hub 22 is made separate from the limiter26, a device for use in connection with the invention is not limited tosuch an arrangement. Forming the hub 22 and limiter 26 integrally from asingle piece of plastic material is an alternative to the example shownin FIGS. 1 and 2. Additionally, it is possible to adhesively orotherwise secure the hub 22 to the limiter 26 in the positionillustrated in FIG. 2 so that the needle assembly 20 becomes a singlepiece unit upon assembly.

[0036] Having a hub 22 and limiter 26 provides the advantage of makingan intradermal needle practical to manufacture. The preferred needlesize is a small Gauge hypodermic needle, commonly known as a 30 Gauge or31 Gauge needle. Having such a small diameter needle presents achallenge to make a needle short enough to prevent undue penetrationbeyond the dennis layer of an animal. The limiter 26 and the hub 22facilitate utilizing a needle 24 that has an overall length that is muchgreater than the effective length of the needle, which penetrates theindividual's tissue during an injection. With a needle assembly designedin accordance herewith, manufacturing is enhanced because larger lengthneedles can be handled during the manufacturing and assembly processeswhile still obtaining the advantages of having a short needle forpurposes of completing an intradermal injection.

[0037]FIG. 3 illustrates the needle assembly 20 secured to a drugcontainer such as a syringe 60 to form the device 10. A generallycylindrical syringe body 62 can be made of plastic or glass as is knownin the art. The syringe body 62 provides a reservoir 64 for containingthe substance to be administered during an injection. A plunger rod 66has a manual activation flange 68 at one end with a stopper 70 at anopposite end as known in the art. Manual movement of the plunger rod 66through the reservoir 64 forces the substance within the reservoir 64 tobe expelled out of the end 40 of the needle as desired.

[0038] The hub 22 can be secured to the syringe body 62 in a variety ofknown manners. In one example, an interference fit is provided betweenthe interior of the hub 22 and the exterior of the outlet port portion72 of the syringe body 62. In another example, a conventional Luer fitarrangement is provided to secure the hub 22 on the end of the syringe60. As can be appreciated from FIG. 3, such needle assembly designed isreadily adaptable to a wide variety of conventional syringe styles.

[0039] This invention provides an intradermal needle injector that isadaptable to be used with a variety of syringe types. Therefore, thisinvention provides the significant advantage of facilitating manufactureand assembly of intradermal needles on a mass production scale in aneconomical fashion.

[0040] Having described the intradermal delivery device including theneedle assembly 20 and drug container 60, its operation and use inpracticing the methods of the present invention for intradermallyinjecting substances is described below.

[0041] Prior to inserting the needle cannula 24, an injection site uponthe skin of the animal is selected and cleaned. Subsequent to selectingand cleaning the site, the forward end 40 of the needle cannula 24 isinserted into the skin of the animal at an angle of generally 90 degreesuntil the skin engaging surface 42 contacts the skin. The skin engagingsurface 42 prevents the needle cannula 42 from passing through thedennis layer of the skin and injecting the substance into thesubcutaneous layer.

[0042] While the needle cannula 42 is inserted into the skin, thesubstance is intradermally injected. The substance may be prefilled intothe syringe 60, either substantially before and stored therein justprior to making the injection. Several variations of the method ofperforming the injection may be utilized depending upon individualpreferences and syringe type. In any event, the penetration of theneedle cannula 42 is most preferably no more than about 1.5 mm becausethe skin engaging surface 42 prevents any further penetration.

[0043] Also, during the administration of an intradermal injection, theforward end 40 of the needle cannula 42 is embedded in the dennis layerof the skin which results in a reasonable amount of back pressure duringthe injection of the substance. This back pressure could be on the orderof 76 psi. In order to reach this pressure with a minimal amount offorce having to be applied by the user to the plunger rod 66 of thesyringe, a syringe barrel 60 with a small inside diameter is preferredsuch as 0.183″ (4.65 mm) or less. The method of this invention thusincludes selecting a syringe for injection having an inside diameter ofsufficient width to generate a force sufficient to overcome the backpressure of the dermis layer when the substance is expelled from thesyringe to make the injection.

[0044] In addition, since intradermal injections are typically carriedout with small volumes of the substance to be injected, i.e., on theorder of no more than 0.5 ml, and preferably around 0.1 ml, a syringebarrel 60 with a small inside diameter is preferred to minimize deadspace which could result in wasted substance captured between thestopper 70 and the shoulder of the syringe after the injection iscompleted. Also, because of the small volumes of substance, on the orderof 0.1 ml, a syringe barrel with a small inside diameter is preferred tominimize air head space between the level of the substance and thestopper 70 during process of inserting the stopper. Further, the smallinside diameter enhances the ability to inspect and visualize the volumeof the substance within the barrel of the syringe.

[0045] Several variations of performing the intradermal injection of thepresent invention (present method) were proven effective during clinicaltrials, the results of which will be explained below. As shown in FIG.8, the syringe 60 may be grasped with a first hand 112 and the plunger66 depressed with the forefinger 114 of a second hand 116.Alternatively, as shown in FIG. 9 the plunger 66 may be depressed by thethumb 118 of the second hand 116 while the syringe 60 is held by thefirst hand. In each of these variations, the skin of the animal isdepressed, and stretched by the skin engaging surface 42 on the limiter26. The skin is contacted by neither the first hand 112 nor the secondhand 116.

[0046] An additional variation has proven effective for administeringthe intradermal injection of the present invention. This variationincludes gripping the syringe 60 with the same hand that is used todepress the plunger 66. FIG. 10 shows the syringe 60 being gripped withthe first hand 112 while the plunger is simultaneously depressed withthe thumb 120 of the first hand 112. This variation includes stretchingthe skin with the second hand 114 while the injection is being made.Alternatively, as shown in FIG. 11, the grip is reversed and the plungeris depressed by the forefinger 122 of the first hand 112 while the skinis being stretched by the second hand 116. However, it is believed thatthis manual stretching of the skin is unnecessary and merely representsa variation out of habit from using the standard technique.

[0047] In each of the variations described above, the needle cannula 24is inserted only about 1.5 mm into the skin of the animal. Subsequent toadministering the injection, the needle cannula 24 is withdrawn from theskin and the syringe 60 and needle assembly 20 are disposed of in anappropriate manner. Each of the variations were utilized in clinicaltrials to determine the effectiveness of both the needle assembly 20 andthe present method of administering the intradermal injection.

[0048] The feasibility of the present method was also proven effectivein animal tests on live swine skin. 50 μg of naked plasmid DNA encodingthe reporter gene, b-galactosidase (b-gal), in fifty μl volume wasdelivered intradermally via “rapid bolus” (approximately 2 μl/sec.).Full thickness skin biopsies were removed at twenty four hours andevaluated for b-gal activity. Twelve separate sites were administeredthe intradermal injections on three separate Yorkshire swine, i.e., foursites were evaluated for each group on each swine. Negative controlsconsisted of delivery of an equivalent dose of an unrelated plasmid DNA.Background b-gal activity in the control group combines data from 30Gauge needle cannula delivered with the standard procedure and 26.6Gauge needle utilizing the limiter 26 and the present method. There wasno discernable difference detected, as there was no difference inactivity between the control groups.

[0049] Mean b-gal activity was determined for both the standardprocedure and the technique of the present method. Mean b-gal activityis represented by the bars, and activity within individual skin sites isrepresented by the dots on the chart shown in FIG. 8. Although there washigh variability in each of the groups, standard procedure, presentmethod, and control, there was a significant increase in b-gal activityin the standard procedure and the present technique compared to thecontrol group. There was no statistical difference in b-gal activitybetween the standard procedure and the present method. Therefore, it wasproven during the animal tests conducted on swine skin that the presentmethod could be used to deliver an intradermal injection at least aseffectively as the standard procedure.

[0050] Subsequent to the swine studies, a clinical trial was conductedon human volunteers to evaluate the effectiveness of the procedure ofthe present invention. Twelve nurses administered intradermal injectionsto 108 healthy subjects. Six of the nurses were very experienced ingiving intradermal injections, and six of the nurses only occasionallygave intradermal injections in which case they only had a baselinecompetency in giving injections prior to the study. Each of the nursesreceived training in the form of videos and practice upon a rubber armon both techniques for making the intradermal injection prior toinitiating the trial.

[0051] The subjects comprised various ethnic groups to determine ifethnicity would have any impact upon functionality. These groupsincluded: Ethnicity Number (percent) Caucasian 67 (16.7%) AfricanAmerican 22 (20.4%) Latino 12 (11.1%) Asian/Pacific 7 (6.5%)

[0052] Eighteen (16.7%) of the subjects were older than sixty years ofage.

[0053] A 26 Gauge ⅜ inch needle cannula with an intradermal bevel wasutilized for the standard procedure, which includes inserting the needleinto the skin at a fifteen degree angle in order to avoid delivering asubcutaneous injection. A 30 Gauge ½ needle with an intradermal bevelwas used with the limiter 26 to administer the intradermal injectionutilizing the present method (generally ninety degree insertion of theneedle cannula) for comparison with the standard procedure. Each of thenurses were instructed to insert the needle cannula into the skin untilthe skin engaging surface 42 made tight contact with the skin,compressing the skin. Each nurse used one of the variations associatedwith the limiter 42 and described above to administer the intradermalinjection using the present method. The variation chosen by each nursewas based upon individual preference.

[0054] Each syringe was filled with 110 μl of saline solution. Thesaline solution was delivered via separate injections into the volarforearm and deltoid region. To determine the effectiveness of theinjection, the site into which the injection was made was examined for asatisfactory tense white wheal resulting from the injection of thesaline solution. The existence of a white wheal indicates a successfulinjection has been made.

[0055] Other variables were analyzed during the trial including theamount of pain experienced by each of the subjects following the salineinjection, the subjects preference for the variation used, and thenurses preferences.

[0056] A tuberculin syringe was filled with 110 μl of saline solution.The air was purged and the filling needle was removed prior to attachingthe appropriate intradermal needle as defined by a randomizationschedule developed for the trial. Each subject was administered eightintradermal injections, two with 100 μl of saline solution into theright and left volar forearms, and two with 100 μl of saline into theright and left deltoid region. One injection from each pair was givenutilizing the present method of the instant invention and one injectionwas given utilizing the standard procedure. Each of the injections wereadministered according to a Randomized Schedule developed for theclinical trial. Good Clinical Practice and Universal Precautions wasadhered to during each of the procedures.

[0057] An injection was considered acceptable if a tense white wheal wasobserved soon after the injection was completed. Completeness of theinjection and post-injection bleeding were also evaluated immediatelyfollowing each injection. The pain perceived by the subject was alsoevaluated immediately after each injection. The subjects were also askedwhich intradermal method was preferred at the conclusion of the eachsession.

[0058] The most significant improvement over the standard procedure wasthe decrease in the amount of pain perceived by each subject. Pain wasmeasured on a twenty point, Gracely Box SL Scale. Each subject was askedto select a point on the table listed below that corresponds to theamount of pain perceived: TABLE 1 Score Sensation  0 No Pain Sensation 1 Faint (pain sensation)  2  3  4 Very Weak  5 Weak  6  7 Very Mild  8Mild  9 10 11 Moderate 12 Barely Strong 13 Slightly Intense 14 15 Strong16 Intense 17 Very Intense 18 Extremely Intense 19 20

[0059]FIG. 9 shows a histogram of the pain perceived by each of thesubjects corresponding to the method used to make the intradermalinjection. The present method proved to be significantly less painfulfor the subjects than the standard method. This is believed to be inpart due to the reduction in the length of needle cannula that isinserted into the skin. The present method results in only 1.5 mm ofneedle cannula being inserted into the skin. The standard procedure,because of the injection angle of fifteen degrees, results in the needlecannula being inserted at least twice that amount to reach the depthrequired to make the injection. Statistically, the present method provedmuch less painful than the standard procedure. The table below indicatesthat the mean pain score for the standard procedure is forty percenthigher than present method described above. The median pain score forthe standard procedure proved to be twice that of the present method.Delivery Method Mean Median Standard Dev. Standard Procedure 7.720 8.0005.423 Present Method 4.460 4.000 4.580

[0060] A visual inspection of the wheal formation subsequent to eachintradermal injection indicated that there was no discernable differencein results between the two methods of making the intradermal injection.A binary analysis was made for each injection site. If no wheal formedafter the intradermal injection was made, a numerical value of zero wasassigned. If a tight white wheal formed after the intradermal injectionwas made, a numerical value of one was assigned. Table 2 listed belowindicates the results of the visual inspection: TABLE 2 Delivery MethodZero One Number of sites Standard Procedure 42 172 214 Present Method 46170 216

[0061] The data collected indicates that with respect to forming a tightwhite wheal the present method performed generally as well as thestandard procedure.

[0062] Each of the nurses was surveyed with respect to their preferencefor the standard procedure or the present method with respect to aparticular injection. The nurses indicated a substantial preference forthe present method in response to several inquiries. The first was aninquiry as to which intradermal injection was thought to be bestrelative to each patient. Table 3 indicates the nurses had a significantoverall preference for the present method: TABLE 3 Delivery MethodNumber Standard Procedure 24 Present Method 81 No Preference  3 TotalResponses 108 

[0063] In response to an inquiry as to the easiest method to administeran intradermal injection, the nurses indicated a significant preferencefor the present method: TABLE 4 Delivery Method Number StandardProcedure  5 Present Method 99 No Preference  4 Total Responses 108 

[0064] In response to an inquiry as to the overall preference betweenthe standard procedure or the present method the nurses indicated asignificant preference for the present method: TABLE 5 Delivery MethodNumber Standard Procedure  3 Present Method 87 No Preference 18 Total108 

[0065] When a preference was requested between the standard procedureand the present method relative to a particular location the intradermalinjection was made, a lo significant preference again was indicated forthe present method. TABLE 6 Preferred injection Delivery Method DeltoidVolar Total Standard Procedure  8  9 17 Present Method 38 52 90 NoPreference  0  0  1 Total 46 61 108 

[0066] A visual inspection was made after each intradermal injection todetermine the amount of leakage of the saline solution from theinjection site. A four point scale was used to rate the amount ofleakage. Zero was selected to indicate no leakage and three was selectedto indicated a significant amount of leakage. The results indicatedthere was no statistically discernable difference between the standardprocedure and the present method. TABLE 7 Rating Delivery Method 0 1 2 3Standard Procedure 142 71 1 0 Present Method 137 68 6 5

[0067] A visual inspection was made of each intradermal injection siteto determine the level of bleeding that resulted from the injection. Thesame four point scale used for the leakage evaluation was used toevaluate the level of bleeding. The data shown in Table 8 indicates thepresent method resulted in less bleeding than the standard proceduredid: TABLE 8 Rating Delivery Method 0 1 2 3 Standard Procedure  98 109 52 Present Method 177  38 0 1

[0068] After the clinical trial was completed, each of the twelve nurseswas surveyed about their overall satisfaction with the present methodwhen compared to the standard procedure. Each of the twelve nursesindicated that it was easy to keep the skin engaging surface 42 againstthe skin of the subject when administering the intradermal injection.Eight of the nurses indicated the overall performance of the presentmethod was excellent. Three indicated the overall performance was betterthan acceptable and only one indicated the performance was less thanacceptable. Eleven of the twelve nurses indicated a preference for thepresent method while only one indicated no preference. All twelve of thenurses indicated the present method was easier to perform than thestandard procedure. The nurses were evenly split as to the ease in ofinjecting the saline solution between the two procedures with two nurseshaving no preference. All twelve nurses indicated the present methodproved easier to keep the needle in the proper place. Eleven of thetwelve nurses indicated it was preferable to give an intradermalinjection at an angle of ninety degrees than fifteen degrees. One nursehad no preference. Seven of the nurses indicated the present method wasmore effective in delivering a proper injection. Two nurses indicatedthe standard procedure was more effective, and three nurses indicated nopreference.

[0069] Accordingly, the method of the present invention may be used tointradermally inject various substance selected from the groupconsisting of drugs, vaccines and the like used in the prevention,diagnosis, alleviation, treatment, or cure of diseases to expose theinjected substance to the microcirculatory blood vasculature and thelymphatic plexuses where the substance can be taken up, absorbed or caninteract with the cells to obtain systemic delivery or an immuneresponse in cases where the substance is either a drug or one or morevaccines. In this way, by targeting the dermal space, the immuneresponse, pharmacokinetics (PK) and pharmacodynamics (PD) parameters ofthe substance can be dramatically altered, which, for example, in thecase of improved bioavailability or improved immune response, can resultin a reduction in the amount of the necessary dose of the substance tobe delivered. These substances may include: (i) drugs such as Alpha-1anti-trypsin, Anti-Angiogenesis agents, Antisense, butorphanol,Calcitonin and analogs, Ceredase, COX-II inhibitors, dermatologicalagents, dihydroergotamine, Dopamine agonists and antagonists,Enkephalins and other opioid peptides, Epidermal growth factors,Erythropoietin and analogs, Follicle stimulating hormone, G-CSF,Glucagon, GM-CSF, granisetron, Growth hormone and analogs (includinggrowth hormone releasing hormone), Growth hormone antagonists, Hirudinand Hirudin analogs such as hirulog, IgE suppressors, Insulin,insulinotropin and analogs, Insulin-like growth factors, Interferons,Interleukins, Leutenizing hormone, Leutenizing hormone releasing hormoneand analogs, Low molecular weight heparin, M-CSF, metoclopramide,Midazolam, Monoclonal antibodies, Narcotic analgesics, nicotine,Non-steroid anti-inflammatory agents, Oligosaccharides, ondansetron,Parathyroid hormone and analogs, Parathyroid hormone antagonists,Prostaglandin antagonists, Prostaglandins, Recombinant solublereceptors, scopolamine, Serotonin agonists and antagonists, Sildenafil,Terbutaline, Thrombolytics, Tissue plasminogen activators, TNF-, andTNF- antagonists; (ii) vaccines, with or without carriers/adjuvants,such as prophylactics and therapeutic antigens (including but notlimited to subunit protein, peptide and polysaccharide, polysaccharideconjugates, toxoids, genetic based vaccines, live attenuated,reassortant, inactivated, whole cells, viral and bacterial vectors) inconnection with, addiction, arthritis, cholera, cocaine addiction,diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps,rubella, varicella, yellow fever, Respiratory syncytial virus, tickborne japanese encephalitis, pneumococcus, streptococcus, typhoid,influenza, hepatitis, including hepatitis A, B, C and E, otitis media,rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis malaria, E-coli, Alzheimers, H. Pylori, salmonella,diabetes, cancer, herpes simplex, human papilloma; and (iii) othersubstances in all of the major therapeutics such as Agents for thecommon cold, Anti-addiction, anti-allergy, anti-emetics, anti-obesity,antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antihistamines, anti-inflammatory agents,antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, vasodilators, including general, coronary, peripheral andcerebral, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents.

[0070] In addition, it should be appreciated that the substancedelivered in accordance with the method of the present invention can bea combination drugs or vaccines, such as for example vaccines against(i) measles, mumps and rubella, (ii) diphtheria, tetanus and acellularpertussis, (iii) hepatitis A and hepatitis B, (iv) haemophilus influenzaB, diphtheria, tetanus and acellular pertussis, (v) haemophilusinfluenza B, hepatitis B, diphtheria, tetanus and acellular pertussis,and (vi) haemophilus influenza B, inactivated polio, diphtheria, tetanusand acellular pertussis which are commonly delivered in combination tothe subcutaneous (SQ) and/or intramuscular (IM) space.

[0071] During SQ or IM injections with a needle, it is generallyrecommended practice to expel or purge any air that may be containedwithin the needle and needle hub prior to the injection. This practiceeliminates the risk of accidentally injecting air into a blood vesselsufficient to create an air embolism into the vasculature. Forintradermal injections, this risk is eliminated because the depth atwhich an intradermal injection is given is not in the region of largeblood vessels into which a needle can penetrate. Therefore, purging theneedle and needle hub of air is not required prior to an intradermalinjection. Furthermore, it is anticipated that purposely injecting asmall volume of air into the intradermal space just prior to injectingthe substance may facilitate the formation of a wheal, which is theindicator of a successful intradermal injection. It is believed thatthis occurs because during an intradermal injection a reasonably highamount of pressure needs to be generated to separate the dermal layersand open a pathway through which the substance can flow. Air, being aless viscous fluid than a substance such as a drug or vaccine, flowseasier into the dermal space, thereby creating a pathway downstream tothe drug or vaccine. This sequential delivery of air followed by drug orvaccine is believed to increase the likelihood of a successfulintradermal injection.

[0072] The present invention also includes the use of the abovesubstances in the preparation of a filled device for making anintradermal injection into the skin of an animal. Accordingly, referringnow to FIG. 10, an example of a way of preparing the filled devicesdesigned according to this invention is schematically illustrated inflow chart format. When the device includes a syringe of the styleillustrated in FIG. 3, the following basic procedure is useful forpreparing prefilling the syringes with a desired substance for such use.

[0073] A supply of syringe barrels 200 includes the desired form ofsyringe, such as those illustrated and discussed above having a firstend and a second end. A locally controlled environment 202 preferably ismaintained in a known manner. The locally controlled environment 202preferably is situated to immediately accept the syringes withoutrequiring any intermediate cleaning or sterilizing steps between thesupply 200 and the environment 202.

[0074] In one example, the syringe barrels are washed with air at 204 toremove any particulates from the syringes. The syringes preferably arethen coated at 206 with a lubricant such as a conventional lubricatingsilicone oil on the inner surface. The lubricant facilitates moving thestopper 70 and plunger rod 66 through the syringe during actual use ofthe device.

[0075] The end of syringes to which the needle assembly 20 willeventually be attached may be capped with a tip cap within theenvironment 202. In one example, tip caps are supplied at 208. The tipcaps are air washed at 210. The cleaned tip caps and syringe barrels areconveyed to an assembly device 212 where the tip caps are secured ontothe syringes. The syringe barrel assemblies are then conveyed to afilling station 214 to be filled with the desired substance.

[0076] Once filled as desired, the stoppers 70 are inserted into theopen end of the syringes at 220. Prior to inserting the stoppers 70,they preferably are assembled with the plunger rods 66 at 222 andlubricated at 224 with a conventional lubricant in a known manner. Theassembled, filled syringes preferably are inspected at 226 for defectsand discharged from the locally controlled environment.

[0077] Where feasible, the syringes typically will be sterilized at 230and packaged at 232 into individual packages or into bulk packagingdepending on the needs of a particular situation. Suitable sterilizationtechniques are known and will be chosen by those skilled in the artdepending on the needs of a particular situation or to accommodate theproperties of a given substance. Sterilizing a device designed accordingto this invention can be completed before or after packaging. Typically,vaccines are not terminally sterilizable, particularly live vaccines.

[0078] Variations of the filling steps are within the scope of thisinvention. For example, the stopper can be inserted first, then fill thesyringe, followed by applying a tip cap. Additionally, the device may befilled just prior to making the injection, particularly in situationswhere the substance to be injected is in a dry or reconstitutable form.

[0079] The actual insertion of the desired substance into the syringebody can be accomplished in any of several known manners. Examplepreparation and filling techniques are disclosed in U.S. Pat. No.6,164,044 to Profano et al.; U.S. Pat. No. 6,189,292 to Odell et al.;U.S. Pat. No. 5,620,425 to Heffernan et al.; U.S. Pat. No. 5,597,530 toSmith et al.; U.S. Pat. No. 5,573,042 to DeHaen; U.S. Pat. No. 5,531,255to Vacca; U.S. Pat. No. 5,519,984 to Beussink et al.; U.S. Pat. No.5,373,684 to Vacca; U.S. Pat. No. 5,256,154 to Liebert et al.; U.S. Pat.No. 5,207,983 to Liebert et al.; and U.S. Pat. No. 4,718,463 to Jurgens,Jr. et al., each of which is incorporated by reference into thisspecification.

[0080] The description given above provides example implementations ofthis invention. Variations and modifications may become apparent tothose skilled in the art that do not necessarily depart from the basisof this invention. The scope of legal protection given to this inventioncan only be determined by studying the following claims.

What is claimed is:
 1. A method of making an intradermal injection intothe skin of an animal to obtain systemic delivery or an immune responsecomprising the steps of: providing a drug delivery device including aneedle cannula having a forward needle tip and said needle cannula beingin fluid communication with a substance contained in said drug deliverydevice and including a limiter portion surrounding said needle cannulaand said limiter portion including a skin engaging surface, with saidneedle tip of said needle cannula extending from said limiter portionbeyond said skin engaging surface a distance equal to approximately 0.5mm to approximately 3.0 mm and said needle cannula having a fixed angleof orientation relative to a plane of the skin engaging surface of thelimiter portion; inserting said needle tip into the skin of an animaland engaging the surface of the skin with said skin engaging surface ofsaid limiter portion such that the skin engaging surface of the limiterportion limits penetration of the needle tip into the dermis layer ofthe skin of the animal; and expelling the substance from said drugdelivery device through the needle tip into the skin of the animal toexpose the injected substance to the microcirculatory blood vasculatureand the lymphatic plexuses.
 2. A method as set forth in claim 1 whereinsaid substance is selected from the group consisting of drugs, vaccinesand the like used in the prevention, diagnosis, alleviation, treatment,or cure of diseases.
 3. A method as set forth in claim 1 wherein saidfixed angle of orientation of said needle cannula is further defined asbeing generally perpendicular to said plane of said skin engagingsurface of the limiter portion within about fifteen degrees.
 4. A methodas set forth in claim 3 wherein said fixed angle of orientation of saidneedle cannula is further defined as being ninety degrees relative tosaid plane of the skin engaging surface of the limiter portion withinabout five degrees.
 5. A method as set forth in claim 2 wherein saidsubstance includes a combination of the drugs or vaccines.
 6. A methodas set forth in claim 5 wherein said substance is selected from acombination of vaccines against (i) measles, mumps and rubella, (ii)diphtheria, tetanus and acellular pertussis, (iii) hepatitis A andhepatitis B, (iv) haemophilus influenza B, diphtheria, tetanus andacellular pertussis, (v) haemophilus influenza B, hepatitis B,diphtheria, tetanus and a cellular pertussis, and (vi) haemophilusinfluenza B, inactivated polio, diphtheria, tetanus and acellularpertussis which are commonly delivered in combination to thesubcutaneous and/or intramuscular space.
 7. A method as set forth inclaim 1 further including the step of selecting an injection sight onthe skin of the animal.
 8. A method as set forth in claim 7 furtherincluding the step of cleaning the injection sight on the skin of theanimal prior to expelling the substance from the drug delivery deviceinto the skin of the animal.
 9. A method as set forth in claim 1 furthercomprising the step of filling the drug delivery device with thesubstance.
 10. A method as set forth in claim 1 further including thestep of pressing said skin engaging surface of said limiter portionagainst the skin of the animal and applying pressure thereby stretchingthe skin of the animal.
 11. A method as set forth in claim 1 furtherincluding the step of withdrawing the needle cannula from the skin afterinjecting the substance.
 12. A method as set forth in claim 1 whereinsaid step of inserting said forward tip into the skin is further definedby inserting said forward tip into the skin to a depth of fromapproximately 1.0 mm to approximately 2.0 mm.
 13. A method as set forthin claim 1 wherein said step of inserting said forward tip into the skinis further defined by inserting said forward tip into the skin to adepth of 1.5 mm±0.2 mm to 0.3 mm.
 14. A method as set forth in claim 1wherein said substance comprises an influenza vaccine.
 15. A method asset forth in claim 1 wherein said substance comprises a hepatitis Bvaccine.
 16. A method as set forth in claim 1 wherein said substancecomprises a rabies vaccine.
 17. A method as set forth in claim 1 whereinsaid substance comprises a cancer vaccine.
 18. A method as set forth inclaim 1 wherein said substance comprises a genetic based vaccine.
 19. Amethod as set forth in claim 1 wherein said substance comprises atuberculin test substance.
 20. A method of making an intradermalinjection with a drug delivery device having a limiter with a skinengaging surface limiting the depth a needle cannula can be insertedinto the skin of an animal to obtain systemic delivery or an immuneresponse comprising the steps of: exposing a forward tip of said needlecannula extending from a limiter beyond a skin engaging surface adistance equal to approximately 0.5 mm to approximately 3.0 mm and saidneedle cannula having a fixed angle of orientation relative to the skinengaging surface of the limiter; inserting said forward tip of theneedle cannula into the skin of the animal at until said skin engagingsurface contacts the skin of the animal; and expelling a substance fromsaid device into the dermis layer of the skin of the animal to exposethe injected substance to the microcirculatory blood vasculature and thelymphatic plexuses.
 21. A method as set forth in claim 20 wherein saidstep of inserting said forward tip into the skin of the animal isfurther defined by inserting said forward tip into the skin at an anglebeing generally perpendicular to the skin.
 22. A method as set forth inclaim 20 wherein said step of inserting said forward tip into the skinof the animal is further defined by inserting said forward tip into theskin at an angle of generally ninety degrees to the skin.
 23. A methodas set forth in claim 20 wherein said fixed angle of orientationrelative to said skin engaging surface is further defined as beinggenerally perpendicular within about fifteen degrees.
 24. A method asset forth in claim 23 wherein said drug delivery device comprises asyringe having a barrel and a plunger received within said barrel andsaid plunger being depressable to expel said substance from saiddelivery device through the forward tip of said needle cannula.
 25. Amethod as set forth in claim 24 wherein said step of expelling thesubstance from said delivery device is further defined by grasping saidhypodermic needle with a first hand and depressing said plunger with anindex finger of a second hand.
 26. A method as set forth in claim 24wherein said step of expelling the substance from said delivery deviceis further defined by grasping said hypodermic needle with a first handand depressing said plunger on said hypodermic needle with a thumb of asecond hand.
 27. A method as set forth in claim 24 wherein said step ofinserting the said forward tip into the skin of the animal is furtherdefined by pressing the skin of the animal with said limiter.
 28. Amethod as set forth in claim 24 further including the step of attachinga needle assembly to a tip of said barrel of said syringe with saidneedle assembly including said needle cannula and said limiter.
 29. Amethod as set forth in claim 28 further including the step of exposingthe tip of said barrel before attaching said needle assembly thereto byremoving a cap from said tip of said barrel.
 30. A method as set forthin claim 20 wherein said animal is human.
 31. A method as set forth inclaim 24 wherein said step of inserting said forward tip of said needleinto the skin of the animal is further defined by simultaneouslygrasping said hypodermic needle with a first hand and pressing saidlimiter against the skin of the animal thereby stretching the skin ofthe animal.
 32. A method as set forth in claim 31 wherein said step ofexpelling the substance is further defined by depressing said plungerwith an index finger of the first hand.
 33. A method as set forth inclaim 31 wherein said step of expelling the substance is further definedby depressing said plunger with a thumb of the first hand.
 34. A methodas set forth in claim 20 further including the step of withdrawing saidforward tip of said needle cannula from the skin of the animal after thesubstance has been injected into the skin of the animal.
 35. A method asset forth in claim 20 wherein said step of inserting said forward tipinto the skin is further defined by inserting said forward tip into theskin to a depth of from approximately 1.0 mm to approximately 2.0 mm.36. A method as set forth in claim 35 wherein said step of insertingsaid forward tip into the skin is further defined by inserting saidforward tip into the skin to a depth of 1.5 mm±0.2 mm to 0.3 mm.
 37. Amethod as set forth in claim 20 wherein said step of exposing saidforward tip of said needle cannula is further defined by removing a capfrom said delivery device.
 38. A method as set forth in claim 20 whereinsaid substance is selected from the group consisting of drugs, vaccinesand the like used in the prevention, diagnosis, alleviation, treatment,or cure of disease.
 39. A method as set forth in claim 38 wherein saiddrugs include Alpha-2 anti-trypsin, Anti-Angiogenesis agents, Antisense,butorphanol, Calcitonin and analogs, Ceredase, COX-II inhibitors,dermatological agents, dihydroergotamine, Dopamine agonists andantagonists, Enkephalins and other opioid peptides, Epidermal growthfactors, Erythropoietin and analogs, Follicle stimulating hormone,G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs(including growth hormone releasing hormone), Growth hormoneantagonists, Hirudin and Hirudin analogs such as hirulog, IgEsuppressors, Insulin, insulinotropin and analogs, Insulin-like growthfactors, Interferons, Interleukins, Leutenizing hormone, Leutenizinghormone releasing hormone and analogs, Low molecular weight heparin,M-CSF, metoclopramide, Midazolam, Monoclonal antibodies, Narcoticanalgesics, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissueplasminogen activators, TNF-, and TNF- antagonist, said vaccines, withor without carriers/adjuvants, include prophylactics and therapeuticantigens (including but not limited to subunit protein, peptide andpolysaccharide, polysaccharide conjugates, toxoids, genetic basedvaccines, live attenuated, reassortant, inactivated, whole cells, viraland bacterial vectors) in connection with, addiction, arthritis,cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease,meningococcus, measles, mumps, rubella, varicella, yellow fever,Respiratory syncytial virus, tick borne japanese encephalitis,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and E, otitis media, rabies, polio, HIV,parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia,non-typeable haemophilus, moraxella catarrhalis, human papilloma virus,tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosismalaria, E-coli, Alzheimers, H. Pylori, salmonella, diabetes, cancer,herpes simplex, human papilloma and like other substances include all ofthe major therapeutics such as agents for the common cold,Anti-addiction, anti-allergy, anti-emetics, anti-obesity,antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antihistamines, anti-inflammatory agents,antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, vasodilators, including general, coronary, peripheral andcerebral, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents.
 40. A method asset forth in claim 38 wherein said substance comprises an influenzavaccine.
 41. A method as set forth in claim 38 wherein said substancecomprises a hepatitis B vaccine.
 42. A method as set forth in claim 38wherein said substance comprises a rabies vaccine.
 43. A method as setforth in claim 38 wherein said substance comprises a cancer vaccine. 44.A method as set forth in claim 38 wherein said substance comprises agenetic based vaccine.
 45. A method as set forth in claim 20 whereinsaid step of expelling the substance from said device into the dermislayer of the skin includes expelling a small volume of air from thedevice into the dermis layer before expelling said substance.
 46. Amethod of making an intradermal injection into the skin of an animalcomprising the steps of: providing a drug delivery device with aprefillable container including a needle cannula having a forward needletip and said needle cannula being in fluid communication with asubstance contained in said prefillable container and including alimiter portion surrounding said needle cannula and said limiter portionincluding a skin engaging surface, with said needle tip of said needlecannula extending from said limiter portion beyond said skin engagingsurface and said needle cannula having a fixed angle of orientationrelative to a plane of the skin engaging surface of the limiter portion;inserting said needle tip into the skin of an animal and engaging thesurface of the skin with said skin engaging surface of said limiterportion such that the skin engaging surface of the limiter portionlimits penetration of the needle tip into the dermis layer of the skinof the animal; and expelling a small volume of air and the substancefrom said drug delivery device through the needle tip into the skin ofthe animal to expose the injected substance to the microcirculatoryblood vascularity and the lymphatic plexuses where the substance can betaken up, absorbed or can interact with the cells to obtain systemicdelivery or an immune response in cases where the substance is either adrug or one or more vaccines.
 47. A method as set forth in claim 46wherein said step of inserting said forward tip into the skin of theanimal is further defined by inserting said forward tip into the skin atan angle being generally perpendicular to the skin within about fifteendegrees.
 48. A method as set forth in claim 47 wherein said step ofinserting said forward tip into the skin of the animal is furtherdefined by inserting said forward tip into the skin at an angle ofgenerally ninety degrees to the skin within about five degrees.
 49. Amethod as set forth in claim 46 wherein said limiter portion has agenerally flat skin engaging surface surrounding said needle tip havingan outside diameter of at least 5 mm.
 50. A method as set forth in claim49 wherein said step of providing a limiter portion is further definedby said forward tip of said needle cannula extending beyond said skinengaging surface a distance equal to approximately 0.5 mm toapproximately 3.0 mm.
 51. A method as set forth in claim 46 wherein saidbarrel of said syringe is made of glass.
 52. A method as set forth inclaim 46 wherein said step of inserting said forward tip into the skinis further defined by inserting said forward tip into the skin to adepth of from approximately 1.0 mm to approximately 2.0 mm.
 53. A methodas set forth in claim 46 wherein said step of inserting said forward tipinto the skin is further defined by inserting said forward tip into theskin to a depth of 1.5 mm±0.2 mm to 0.3 mm.
 54. A method as set forth inclaim 46 wherein said substance is selected from the group consisting ofdrugs, vaccines and the like used in the prevention, diagnosis,alleviation, treatment, or cure of diseases.
 55. A method as set forthin claim 46 wherein said substance is selected from the group consistingof drugs, vaccines and the like used in the prevention, diagnosis,alleviation, treatment, or cure of diseases.
 56. A method as set forthin claim 55 wherein said substances includes a combination of drugs orvaccines.
 57. A method as set forth in claim 56 wherein said substanceis selected from vaccine combinations against (i) measles, mumps andrubella, (ii) diphtheria, tetanus and acellular pertussis, (iii)hepatitis A and hepatitis B, (iv) haemophilus influenza B, diphtheria,tetanus and acellular pertussis, (v) haemophilus influenza B, hepatitisB, diphtheria, tetanus and acellular pertussis, and (vi) haemophilusinfluenza B, inactivated polio, diphtheria, tetanus and acellularpertussis which are commonly delivered in combination to thesubcutaneous and/or intramuscular space.